In October 2013, the World Medical Association (WMA) approved the final new version of the Declaration of Helsinki (DoH). Since its adoption in 1964, this document has served as the foundation basis for the ethical conduct of medical research in humans. The document has been revised eight (8) times so far since 1964, most recently in 2008.

According to the WMA, the current changes “provide for more protection for vulnerable groups and all participants by including the issue of compensation, more precise and specific requirements for post-study arrangements and a more systematic approach to the use of placebos.” 2014 will be the 50th anniversary of the first edition of the Declaration from 1964. There is a nice editorial in the Journal of the American Medical Association from November 2013 that discusses the newest version along with the history of the document at: JAMA article .

For more details on the final document and to obtain a copy visit: WMA page

This guidance document reiterates the FDA current thinking on a risk-based approach to monitoring. There is a growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% data verification to ensure subject protection and overall study quality. This final guidance goes into some detail on different methods that can be used to put in place an effective monitoring plan for a clinical study. This guidance makes clear that sponsors can use a variety of approaches to fulfill their responsibilities for monitoring investigator conduct and performance in investigational new drug (IND) studies conducted under 21 CFR §312 or investigational device exemption (IDE) studies conducted under 21 CFR §812. The guidance describes strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively.

FDA recognizes that this guidance places greater emphasis on centralized monitoring than appeared feasible at the time ICH E6 was finalized. However, FDA considers the approach to monitoring described in this guidance to be consistent with ICH E6 and ISO 14155:2011 (devices).

Again the guidance does not suggest eliminating on-site visits. Rather, what it operationalizes and supports is the role of centralized review of data along with on-site visits to enhance quality. The guidance specifically encourages greater use of centralized monitoring methods where appropriate. CRAs will still make on-site visits, but they will spend less time focusing on some issues, like data consistency that can easily be checked by a computer, and focus on items that need a close live eye view to verify, like ICF forms, visit dates, or AEs not reported, etc. The guidance suggests that sponsors should prospectively identify critical data and processes that if inaccurate, not performed, or performed incorrectly would threaten the protection of human subjects or the integrity of the study results.

This guidance reflects FDA’s general approach in recent years to risk based approach to quality in a number of areas. This includes manufacturing quality, safety reporting and even FDA’s own inspection planning in CDER is moving to a risk based approach. The guidance discusses risk assessment as applied in the context of clinical monitoring. Risk assessment generally involves identifying risks, analyzing risks, and then determining whether risks need to be modified by implementing controls. The key tool in risk assessment and planning is to develop and implement a formal monitoring plan for each study that addresses the risk plan in writing.

The guidance also emphasizes that one of the key risk tools in obtaining quality data is a well designed and articulated protocol and related tools such as the informed consent document and case report forms.

In April 2013, the World Medical Association (WMA) released a draft of the revised language for a new version of the Declaration of Helsinki (DoH). Since its adoption in 1964, this document has served as the foundation basis for the ethical conduct of medical research in humans. The document has been revised eight (8) times so far since 1964, most recently in 2008. The draft is proposed for finalization and release later in 2013.

According to the WMA, the current round of proposed changes is intended “to provide for more protection for vulnerable groups and all participants by including the issue of compensation, more precise and specific requirements for post-study arrangements and a more systematic approach to the use of placebos.” The working group will then produce a final revised draft to be considered by the WMA’s ethics committee and Council at their meetings in Fortaleza, Brazil in October 2013, when a decision will be taken whether to forward the document to the WMA Assembly at the same meeting for adoption.

For more details on the proposed changes and to see a draft of the language visit: WMA page

In February 2013 the FDA proposed to amend the regulations in §814 regarding the acceptance of data from medical device trials. The current regulation in §814.15 states that FDA will accept the data if the data are valid and the investigator has conducted the studies in conformance with the Declaration of Helsinki or the laws and regulations of the country in which the research is conducted, whichever accords greater protection to the human subjects. In addition, the regulations regarding 510K submissions and investigational device exemptions (IDE) do not address the acceptance by FDA of data generated outside of the US.

FDA will accept information on clinical studies conducted outside the United States to support an IDE or a device marketing application (510K or PMA) or other submission if the data are valid and the information specified in other sections is submitted. The first item is a statement should be provided that all such studies have been conducted in accordance with good clinical practice (GCP). For the purposes of this section, GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected. The sponsor or applicant who submits data from a clinical study conducted outside the United States in support of an IDE or a device marketing application or submission, in addition to information required, shall provide a description of the actions the sponsor or applicant took to ensure that the research conformed to GCP.

When implemented, this regulation will be similar in language and scope to the updated language added to the IND/NDA regulations in 2008 in §312.120. It will thus provide greater consistency in expectations for the conduct of studies outside of the US for drugs, devices and biologics by defining a single standard of conduct as good clinical practice (GCP). As with the drug regulations, it will eliminate a direct reference to the Declaration of Helsinki (DoH) and a particular version of the declaration in the regulations. This is not to imply that the FDA and the US government do not support the Declaration of Helsinki. On the contrary, the DoH is still the foundation document for the ethical conduct of clinical trials. It is in fact referenced in the ICH GCP Guideline (E6), the ISO 141255 Guideline for Medical Device clinical trials, the Pan American Health Organization (PAHO), World Health Organization (WHO) and CIOMS Guidances on good clinical practice and ethical considerations in clinical trials as the ethical basis for these Guidelines. Collectively, these documents all define a standard of conduct known as GCP and documents that the FDA references as GCP.

No timetable is provided for the finalization and implementation of these proposed changes to the regulations. It typically take 1-2 years for all the comments and feedback to be reviewed and evaluated before a final regulation is issued. Once issued it typically takes effect within 6 months of publication.

The 2013 Good Clinical Practice Question & Answer (Q&A) Guide – For CRAs, investigators/sites, auditors, compliance, legal, and other clinical professionals is now available. I serve as the Editor-in-Chief of this publication. Published by Barnett International (GCP Q&A Book), this book is considered by most persons in the field as the most authoritative source of GCP information available. It is now also available both as a print version, spiral bound book or as an electronic book resource. It has been updated and revised for 2013 to reflect the most current information regarding GCP issues.

The Department of Health and Human Services (DHHS) has released a long-anticipated final rule modifying its regulations regarding the Health Insurance Portability and Accountability Act, (HIPAA) more commonly known by its acronym, HIPAA.

HIPAA contains a number of data privacy protections, most notably the “privacy rule,” which closely regulates how protected health information (PHI)—any health-related information about a person that can personally identify them—may be used by an entity covered by the law. Most disclosures outside of ones intended to facilitate payments or treatment directly require authorization from the patient in order to proceed. The rule, released on 18 January 2013, is substantial both in length and effect. The final rule with four distinct rules combined into one affects a huge number of industries, including companies conducting clinical trials.

Companies will be further restricted from using some of the information they obtain from patients, for example, and can no longer sell PHI or use it for marketing or fundraising purposes.

Impact on Clinical Trials
Clinical trial sites will also be exempted from certain requirements, such as those limiting the use of single authorizations (“compound authorizations”) for the release of PHI.

“Permitting the use of protected health information is part of the decision to receive care through a clinical trial, and health care providers conducting such trials are able to condition research-related treatment on the individual’s willingness to authorize the use or disclosure of protected health information for research associated with the trial,” DHHS explained in its rule.

However, trial sites will still be prohibited from using compound authorizations for tissue banking purposes, though they can ask for such samples in a separate authorization form or in the same package so long as it is unconditional. DHHS suggested the use of separate check boxes and authorization signature lines for entities that wish to simplify the enrollment process.

These exemptions could prove crucial to companies hoping to use collected data for “corollary research activity,” such as for research databases or repositories used to find common genetic markers or other information used to generate new information on therapies.

Many of the remaining provisions of the final rule, if not already in effect, will come into effect on 26 March 2013, and require full compliance 180 days after that date.

Other Provisions
Patients would also have the right to receive electronic copies of their health information and be permitted to restrict insurance companies from finding out about healthcare received but paid for out of pocket in full. The latter could be construed as a potential incentive for some clinical trials, as some patients now are wary of participating if it has the potential to increase their premiums.

It would also become easier to release information to the family of deceased patients—a potential benefit (or liability) to those testing products on patients who die in the midst of treatment.

Other parts of the rule focus more on compliance. Those found to have violated HIPAA provisions, for instance, will be subject to tiered and increased civil monetary penalties. Entities will also be bound by an objective definition of what constitutes a leak of information that could negatively impact a patient.

The 2012 Good Clinical Practice Question & Answer (Q&A) Guide – For CRAs, investigators/sites, auditors, compliance, legal, and other clinical professionals has been published. I serve as the Editor-in-Chief of this publication. Published by Barnett International (GCP Q&A Book), this book is considered by most persons in the field as the most authoritative source of GCP information available. It is now also available both as a print version, spiral bound book or as an electronic book resource. It has been updated and revised for 2012 to reflect the most current information regarding GCP issues.

The FDA Safety and Innovation Act was signed into law by the President on July 9, 2012. This law reauthorizes user fees for device and drugs and establishes user fees for biosimilar products and generic drugs. There are also a number of other initiatives and incentives added to FDA Law. One of the key points is that in the next few years all submissions to FDA for drugs and biologics will have to be electronic, no more paper submissions.

The Congress is in the process of voting and reauthorizing the Prescription Drug User Fee Act (PDUFA) for another five years. This law, originally passed in 1992, allows FDA to collect fees associated with submission and review of a New Drug Application along with product and establishment fees. The Act requires that Congress reauthorize the law every five years. Each cycle, the reauthorization has included a review and reexamination of FDA progress in meeting review goals and protecting the public. Over the years, new aspects of FDA oversight have been included as part of the reauthorization, including the addition of REMS, requirements for post-approval studies and the development of pediatric information for labels. The success of the PDUFA program for drugs (and biologics) led to the institution of User Fees for medical devices in 2002 (MDUFMA). New for 2013 going forward will be user fees for generic drugs for the first time, as well as a novel structure for user fees for biosimilar products. The law is expected to be finalized this summer to be ready for implementation in the next Fiscal Year, starting October 1, 2012. Stay tuned for more details.

This guidance document is designed to help industry develop a proper monitoring plan to assure quality and reliable data during the conduct of clinical studies. Monitoring of a clinical study is required by regulation in 312.50 and 812.40, but the regulations do not describe what this means, how often and what steps are involved. This has always been part of industry practice and will vary from company to company. FDA also expects ‘adequate oversight’ of a clinical trial but also never defined what is adequate. Adequate monitoring has always been the issue for the proper conduct and oversight of clinical trials. What has happened over the years is that companies chose to interpret this to mean, lots of visits and 100% SDV is the only way to be adequate. However, if this were truly working, there would be no warning letters to PIs for study conduct issues, Right??

There are companies who have chosen to take a risk based approach for years and focus on the important stuff and have had acceptable studies for FDA, based on lack of audit findings. So clearly this approach can work. What I think we are seeing is FDA acknowledging that the old way is not the only way, and the use of existing (and future) technology can enhance monitoring to improve oversight and quality. Remember in 1988 when the original guidance was issued, there was no email, no internet, no eCRF, cell phones were almost nonexistent and smart phones were those wired devices on your desk where you had buttons to answer more than one line and place a call on hold. The greatest ‘e-technology’ we had at that time was the Fax machine.

So, I do not see it eliminating on-site visits, as many others have also pointed out and concurred. What I think this operationalizes and supports, is the role of centralized review of data along with on-site visits to enhance quality. CRAs will still need to make on-site visits, but they can spend less time focusing on some issues, like data consistency that can easily be checked by a computer, and focus on items that need a close live eye view to verify, like ICF forms, visit dates, or AEs not reported etc. No eCRF system and this risk based approach, can detect something if it is not captured and reported.

The other important aspect of this new draft guidance is that it again reflects FDA’s general approach in recent years to risk based approach to quality in a number of areas. This includes manufacturing quality, safety reporting and even FDA’s own inspection planning in CDER is moving to a risk based approach.